Project Summary Unlike type 2 diabetes, where prevention is possible, type 1 diabetes (T1D) is currently neither preventable nor curable and its incidence continues to rise approximately 3% per year. Thus, the continuing investigation of T1D complications remains imperative. The Epidemiology of Diabetes Complications (EDC) study has examined the prevalence and incidence of, and risk factors contributing to, T1D complications for 30 years. The study population is a well-defined cohort of childhood-onset T1D identified from the Children's Hospital of Pittsburgh Registry (diagnosis: 1950-80). All 658 participants attending a clinical exam at study entry (1986-88) have been subsequently followed for up to 30 years, leading to over 180 peer-reviewed publications. As of 6/1/2018, 220 (33%) have died and 396 (60%) are in active follow-up at a mean age of 56 (range 39-77) and T1D duration of 48 (38-68) years. With this renewal, we aim to preserve the infrastructure of the EDC study, allowing the continued use of the vast available resources collected over 30 years in furthering our understanding of the pathophysiology of T1D complications. A major objective is to continue documentation of the natural history of complications, with annual survey follow-up of active participants, which will also allow the continued documentation of disability, an important manifestation of aging. Another major objective is to use novel analytic methods (causal inference, networking and mixed graphical modeling) to explore this extensive data set of over 150 risk factors and 12 major outcomes. Given the amalgamation of repeated risk factor and outcome measures during more than 30 years of follow-up, these more complex analyses will help identify an interplay of factors across scales (clinical, blood biomarkers, molecular/genetic, etc.) may discover new mechanisms of complication development and thus point to new interventional strategies. We will also comprehensively evaluate the hypothesis that T1D is a state of accelerated aging by comparing novel, to the T1D field biomarkers of aging, and, with separate funding, DNA methylation age, between participants with T1D and non-diabetic control participants of the RETRO HDL study (stored samples/data will be used). Finally, given our findings of a strong, direct association between the Haptoglobin 2 allele and morbidity and mortality from cardiovascular and renal complications, we will assess whether the concentrations of biomarkers of aging differ across Haptoglobin genotypes in this T1D cohort. The proposed renewal will thus allow, for the first time, documentation of ?elderly? childhood-onset T1D and provide a unique insight into the accelerated aging seen in the T1D population.